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Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin)
Published on: January 20, 2016
Rational design of anthracene-based DNA binders
Michael R Duff1, Vamsi K Mudhivarthi, Challa V Kumar
1Department of Chemistry, U-3060, 55 North Eagleville Road, University of Connecticut, Storrs, Connecticut 06269-3060, USA.
The Journal of Physical Chemistry. B
|February 6, 2009
Summary
Researchers developed a systematic method to design DNA-binding anthracene molecules. Adding methylene groups predictably increases binding affinity and modifies enthalpy, aiding rational drug design.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biophysics
Background:
- Rational design of DNA-binding ligands is crucial for developing novel therapeutics.
- Anthracene derivatives are a class of compounds with potential DNA-binding properties.
Purpose of the Study:
- To develop a simple, systematic, and quantitative approach for designing DNA-binding anthracene derivatives.
- To understand the relationship between structural features of anthracene derivatives and their DNA-binding thermodynamics.
Main Methods:
- Systematic synthesis and modification of anthracene probes with varying numbers of methylene groups.
- Isothermal titration calorimetry (ITC) or similar techniques to measure binding thermodynamics (DeltaG°, DeltaH°).
- Ionic strength studies to deconvolve specific and non-specific binding contributions.
Main Results:
- Introduction of methylene groups in anthracene derivatives significantly enhances DNA-binding affinity.
- Each methylene group contributes approximately -1.49 kcal/mol to the intrinsic free energy of binding.
- Methylene groups also predictably influence binding enthalpy, contributing +0.28 kcal/mol per group.
Conclusions:
- A quantitative relationship exists between the number of methylene groups and the binding affinity/enthalpy of anthracene-DNA interactions.
- This provides a powerful tool for the rational design and fine-tuning of novel DNA-binding ligands.
- The findings are applicable to the development of new drugs targeting DNA.
